Cystic fibrosis (CF) impacts 30,000 individuals in the United States and 70,000 individuals worldwide (Patient registry: Annual Data Report. Cystic Fibrosis Foundation 2012; Bethesda, Md.). Mortality from the disease primarily occurs due to progressive respiratory infection and an excessive inflammatory response in the CF lung (Davis P B, Drumm M, Konstan M W. Cystic fibrosis. Am J Respir Crit Care Med 1996; 154:1229-56; Chmiel J F, Berger M, Konstan M W. The role of inflammation in the pathophysiology of CF lung disease. Clin Rev Allergy Immunol 2002; 23:5-27). As the disease progresses, patients experience increasingly frequent pulmonary exacerbations, which in turn increase risk for subsequent decline (Sanders D B, Hoffman L R, Emerson J, et al. Return of FEV1 after pulmonary exacerbation in children with cystic fibrosis. Pediatr Pulmonol 2010; 45:127-34; Sanders D B, Bittner R C, Rosenfeld M, Hoffman L R, Redding G J, Goss C H. Failure to recover to baseline pulmonary function after cystic fibrosis pulmonary exacerbation. Am J Respir Crit Care Med 2010; 182:627-3; Waters V, Stanojevic S, Atenafu E G, et al. Effect of pulmonary exacerbations on long-term lung function decline in cystic fibrosis. Eur Respir J 2012; 40:61-6). The number of pulmonary exacerbation episodes suffered in a single year correlates highly with lung function decline in the ensuing three years for both children and adults (Sanders D B, Hoffman L R, Emerson J, et al. Return of FEV1 after pulmonary exacerbation in children with cystic fibrosis. Pediatr Pulmonol 2010; 45:127-34; Sanders D B, Bittner R C, Rosenfeld M, Hoffman L R, Redding G J, Goss C H. Failure to recover to baseline pulmonary function after cystic fibrosis pulmonary exacerbation. Am J Respir Crit Care Med 2010; 182:627-32; Sanders D B, Bittner R C, Rosenfeld M, Redding G J, Goss C H. Pulmonary exacerbations are associated with subsequent FEV1 decline in both adults and children with cystic fibrosis. Pediatr Pulmonol 2011; 46:393-400). An exceedingly high number of CF patients, 1 in 4, do not recover to baseline Forced Expiratory Volume in 1 second (FEV1) after standard treatment of acute pulmonary exacerbations (APE) (Sanders D B, Hoffman L R, Emerson J, et al. Return of FEV1 after pulmonary exacerbation in children with cystic fibrosis. Pediatr Pulmonol 2010; 45:127-34).
Cystic fibrosis (CF) is the most common lethal inherited disease in the western world. While life expectancies have increased to nearly 40 years, respiratory failure still accounts for >80% of deaths from the disease, usually in young adults in the third or fourth decade of life. The triad of airway obstruction with mucus, chronic endobronchial infection with pathogens such as Pseudomonas aeruginosa, and severe airway inflammation, are the major pathogenic factors in CF lung disease (Konstan, 1998, Clin Chest Med 19(3):505-13, vi). Given the shortage of solid organs for transplantation in end stage lung disease, there is a critical need for effective anti-microbial and anti-inflammatory therapies to mitigate progression of disease in this young population.
The rendering of rapid and efficient clinical trials in CF and other diseases associated with pulmonary exacerbation, is hampered, in part, by the lack of sensitive measures of treatment response. In general, severity of exacerbation episodes are estimated based on spirometry and symptoms (Shoki A H, Mayer-Hamblett N, Wilcox P G, Sin D D, Quon B S. Systematic review of blood biomarkers in cystic fibrosis pulmonary exacerbations. Chest 2013; 144:1659-70). No mechanism exists to quantify or to “stage” the degree of inflammation in a particular individual, in a manner which predicts their risk from the infectious episode. Such a tool could potentially capture the marked heterogeneity in exacerbations between individuals, as well as within an individual, from one episode to another. Identification of molecular phenotypes underlying exacerbation heterogeneity would improve understanding of the individual host's response to pulmonary infection, ideally allowing customization of treatment approaches during the episode and beyond it. In current practice, consensus guidelines for APE treatment are relatively limited, in part due to a lack of definitions and classifiers of APE severity. There are no class A recommendations, and recommendations regarding key aspects of treatment are deemed “indeterminate” for the following: drug selection, quantity of antimicrobial agents, dosing strategies, and duration of antibiotics (Flume P A, Mogayzel P J, Jr., Robinson K A, et al. Cystic fibrosis pulmonary guidelines: treatment of pulmonary exacerbations. Am J Respir Crit Care Med 2009; 180:802-8). The ability to readily identify and quantify host inflammatory responses may allow stratification of treatment according to underlying biology, facilitating the conduct of clinical trials to identify strategies to improve current APE outcomes.
At present, there are no known reliable and sensitive molecular markers which can be used to categorize subject subgroups at risk for increased pulmonary exacerbation and/or disease progression, including increased risk of mortality and/or morbidity due to severe acute pulmonary exacerbation. There is a critical need in CF to better understand the impact a particular exacerbation has on a patient's overall disease course.